SCID mice carry a VDJ-recombinase associated defect and many of their immune cells fail to rearrange both T cell receptor and immunoglobulin genes. We have transplanted thyroid cells from patients, with and without autoimmune thyroid disease, into the subcutaneous tissue of SCID mice and subsequently transplanted peripheral blood mononuclear cells (PBMC) from the same donor into the peritoneal cavity. The transplanted immune cells secreted large quantities of human IgG and autoantibodies to human thyroid-peroxidase (TPO) and the thyroid cells secreted human thyroglobulin into the murine serum. We have, therefore, introduced an adult human immune repertoire into an animal hosting a functioning autologous thyroid. We now plan a number of unique approaches which, we believe, will make this an important model for the study of human autoimmune thyroid disease. We will (1) determine if human lymphocytes "home" to human thyroid cell transplants in these SCID mice, (2) evaluate, using the polymerase chain reaction technique T cell receptor V alpha and beta gene usage by T cells which accumulate within the human thyroid cells, (3) investigate thyroid antigen presentation in SCID mice with macrophage transplants or human thyroid cell transplants, and (4) explore mechanisms for prolonging graft survival in SCID mice by examining the reduction in natural killer (NK) cell activity induced by monoclonal antibody treatment and also a new strain of SCID mice with a reduced NK cell population (NOD/SCID). The human thyroid transplanted SCID mouse is more than an animal model, it contains and preserves in a potentially functional state of elements of a human thyroid-immune axis. This means that, for the first time, we can study in vivo, a model of the human immune system and its repertoire interacting with the target organ.